Top

Published in:

01-05-2016 | Review Article

Liver progenitor cells-mediated liver regeneration in liver cirrhosis

Authors: Haitao Shang, Zhijun Wang, Yuhu Song

Published in: Hepatology International | Issue 3/2016

Abstract

Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury. In cirrhotic liver where hepatocytes proliferation is compromised, liver progenitor cells (LPCs) are activated and then differentiated into hepatocytes and cholangiocytes, leading to the generation of regenerative nodules and functional restoration. Here, we summarize and discuss recent findings on the mechanisms underlying LPCs-mediated regeneration in liver cirrhosis. Firstly, we provide recent research on the mechanism underlying LPCs activation in severe or chronic liver injury. Secondly, we present new and exciting data on exploring the origin of LPCs, which reveal that the hepatocytes give rise to duct-like progenitors that then differentiate back into hepatocytes in chronic liver injury or liver cirrhosis. Finally, we highlight recent findings from the literature exploring the role of LPCs niche in directing the behavior and fate of LPCs. This remarkable insight into the cellular and molecular mechanisms of LPCs-mediated regeneration in liver cirrhosis will provide a basis for translating this knowledge into clinical application.

Wang Z, Song Y, Tu W, He X, Lin J, Liu F. Beta-2 spectrin is involved in hepatocyte proliferation through the interaction of TGFbeta/Smad and PI3 K/AKT signalling. Liver Int 2012;32:1103–1111CrossRefPubMed

Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 2009;137:466–481CrossRefPubMedPubMedCentral

Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 2014;146:349–356CrossRefPubMed

Katoonizadeh A, Poustchi H, Malekzadeh R. Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives. Liver Int 2014;34:1464–1472CrossRefPubMed

Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepatology 2014;59:1617–1626CrossRefPubMed

Demetris AJ, Seaberg EC, Wennerberg A, Ionellie J, Michalopoulos G. Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes. Am J Pathol 1996;149:439–448PubMedPubMedCentral

Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 1999;154:537–441CrossRefPubMedPubMedCentral

Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 2006;26:1225–1233CrossRefPubMed

Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, et al. Regeneration of hepatocyte ‘buds’ in cirrhosis from intrabiliary stem cells. J Hepatol 2003;39:357–364CrossRefPubMed

10.

Wang Z, Liu F, Tu W, Chang Y, Yao J, Wu W, et al. Embryonic liver fodrin involved in hepatic stellate cell activation and formation of regenerative nodule in liver cirrhosis. J Cell Mol Med 2012;16:118–128CrossRefPubMedPubMedCentral

11.

Jung Y, Witek RP, Syn WK, Choi SS, Omenetti A, Premont R, et al. Signals from dying hepatocytes trigger growth of liver progenitors. Gut 2010;59:655–665CrossRefPubMedPubMedCentral

12.

Li D, Cen J, Chen X, Conway EM, Ji Y, Hui L. Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice. Hepatology 2013;58:2109–2121CrossRefPubMed

13.

Thenappan A, Li Y, Kitisin K, Rashid A, Shetty K, Johnson L, et al. Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver. Hepatology 2010;51:1373–1382CrossRefPubMedPubMedCentral

14.

Viebahn CS, Benseler V, Holz LE, Elsegood CL, Vo M, Bertolino P, et al. Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury. J Hepatol 2010;53:500–507CrossRefPubMed

15.

Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, et al. TWEAK induces liver progenitor cell proliferation. J Clin Invest 2005;115:2330–2340CrossRefPubMedPubMedCentral

16.

Tirnitz-Parker JE, Viebahn CS, Jakubowski A, Klopcic BR, Olynyk JK, Yeoh GC, et al. Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology 2010;52:291–302CrossRefPubMed

17.

Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, et al. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 2011;25:1193–1203CrossRefPubMedPubMedCentral

18.

Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013;494:247–250CrossRefPubMedPubMedCentral

19.

Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011;43:34–41CrossRefPubMed

20.

Espanol-Suner R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 2012;143(1564–1575):e1567

21.

Kordes C, Sawitza I, Muller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H, et al. CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 2007;352:410–417CrossRefPubMed

22.

Kordes C, Sawitza I, Gotze S, Herebian D, Haussinger D. Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest 2014;124:5503–5515CrossRefPubMedPubMedCentral

23.

Yang L, Jung Y, Omenetti A, Witek RP, Choi S, Vandongen HM, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 2008;26:2104–2113CrossRefPubMedPubMedCentral

24.

Michelotti GA, Xie G, Swiderska M, Choi SS, Karaca G, Kruger L, et al. Smoothened is a master regulator of adult liver repair. J Clin Invest 2013;123:2380–2394PubMedPubMedCentral

25.

Swiderska-Syn M, Syn WK, Xie G, Kruger L, Machado MV, Karaca G, et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014;63:1333–1344CrossRefPubMedPubMedCentral

26.

Yanger K, Knigin D, Zong Y, Maggs L, Gu G, Akiyama H, et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014;15:340–349CrossRefPubMedPubMedCentral

27.

Sekiya S, Suzuki A. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol 2014;184:1468–1478CrossRefPubMed

28.

Schaub JR, Malato Y, Gormond C, Willenbring H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 2014;8:933–939CrossRefPubMedPubMedCentral

29.

Tarlow BD, Finegold MJ, Grompe M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 2014;60:278–289CrossRefPubMedPubMedCentral

30.

Rodrigo-Torres D, Affo S, Coll M, Morales-Ibanez O, Millan C, Blaya D, et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 2014;60:1367–1377CrossRefPubMedPubMedCentral

31.

Malato Y, Naqvi S, Schurmann N, Ng R, Wang B, Zape J, et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J Clin Invest 2011;121:4850–4860CrossRefPubMedPubMedCentral

32.

Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM, Finegold MJ, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 2014;15:605–618CrossRefPubMedPubMedCentral

33.

Michalopoulos GK, Barua L, Bowen WC. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 2005;41:535–544CrossRefPubMedPubMedCentral

34.

Tanimizu N, Nishikawa Y, Ichinohe N, Akiyama H, Mitaka T. Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration. J Biol Chem 2014;289:7589–7598CrossRefPubMedPubMedCentral

35.

Kordes C, Haussinger D. Hepatic stem cell niches. J Clin Invest 2013;123:1874–1880CrossRefPubMedPubMedCentral

36.

Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 2008;47:1994–2002CrossRefPubMedPubMedCentral

37.

Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, et al. The canals of Hering and hepatic stem cells in humans. Hepatology 1999;30:1425–1433CrossRefPubMed

38.

Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 2004;39:1739–1745CrossRefPubMed

39.

Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010;59:645–654CrossRefPubMedPubMedCentral

40.

Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013;123:1887–1901CrossRefPubMedPubMedCentral

41.

Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 2009;49:1625–1635CrossRefPubMed

42.

Pintilie DG, Shupe TD, Oh SH, Salganik SV, Darwiche H, Petersen BE. Hepatic stellate cells’ involvement in progenitor-mediated liver regeneration. Lab Invest 2010;90:1199–1208CrossRefPubMedPubMedCentral

43.

Ruddell RG, Knight B, Tirnitz-Parker JE, Akhurst B, Summerville L, Subramaniam VN, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology 2009;49:227–239CrossRefPubMed

44.

Lin N, Tang Z, Deng M, Zhong Y, Lin J, Yang X, et al. Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells. Biochem Biophys Res Commun 2008;372:260–265CrossRefPubMed

45.

Takase HM, Itoh T, Ino S, Wang T, Koji T, Akira S, et al. FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. Genes Dev 2013;27:169–181CrossRefPubMedPubMedCentral

46.

Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 2012;18:572–579CrossRefPubMedPubMedCentral

47.

Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, et al. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut 2010;59:247–257CrossRefPubMed

48.

Streetz KL, Tacke F, Leifeld L, Wustefeld T, Graw A, Klein C, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology 2003;38:218–229CrossRefPubMed

49.

Zhu NL, Asahina K, Wang J, Ueno A, Lazaro R, Miyaoka Y, et al. Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration. J Biol Chem 2012;287:10355–10367CrossRefPubMedPubMedCentral

50.

Deng X, Chen YX, Zhang X, Zhang JP, Yin C, Yue HY, et al. Hepatic stellate cells modulate the differentiation of bone marrow mesenchymal stem cells into hepatocyte-like cells. J Cell Physiol 2008;217:138–144CrossRefPubMed

51.

Nagai H, Terada K, Watanabe G, Ueno Y, Aiba N, Shibuya T, et al. Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells. Biochem Biophys Res Commun 2002;293:1420–1425CrossRefPubMed

52.

Wang Y, Yao HL, Cui CB, Wauthier E, Barbier C, Costello MJ, et al. Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates. Hepatology 2010;52:1443–1454CrossRefPubMedPubMedCentral

53.

Evarts RP, Hu Z, Fujio K, Marsden ER, Thorgeirsson SS. Activation of hepatic stem cell compartment in the rat: role of transforming growth factor alpha, hepatocyte growth factor, and acidic fibroblast growth factor in early proliferation. Cell Growth Differ 1993;4:555–561PubMed

54.

Ishikawa T, Factor VM, Marquardt JU, Raggi C, Seo D, Kitade M, et al. Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology 2012;55:1215–1226CrossRefPubMedPubMedCentral

55.

Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, et al. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun 2007;363:247–252CrossRefPubMedPubMedCentral

56.

Chobert MN, Couchie D, Fourcot A, Zafrani ES, Laperche Y, Mavier P, et al. Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats. Lab Invest 2012;92:135–150CrossRefPubMedPubMedCentral

57.

Kuramitsu K, Sverdlov DY, Liu SB, Csizmadia E, Burkly L, Schuppan D, et al. Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. Am J Pathol 2013;183:182–194CrossRefPubMedPubMedCentral

58.

Tirnitz-Parker JE, Olynyk JK, Ramm GA. Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses. Hepatology 2014;59:1198–1201CrossRefPubMed

59.

Chen HN, Wang DJ, Ren MY, Wang QL, Sui SJ. TWEAK/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-small ka, CyrillicB pathway. Mol Biol Rep 2012;39:8231–8241CrossRefPubMed

60.

Issa R, Zhou X, Trim N, Millward-Sadler H, Krane S, Benyon C, et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J 2003;17:47–49PubMed

61.

Kallis YN, Robson AJ, Fallowfield JA, Thomas HC, Alison MR, Wright NA, et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut 2011;60:525–533CrossRefPubMed

62.

Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M, Rossi M, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology 2011;54:2159–2172CrossRefPubMed

63.

Paku S, Nagy P, Kopper L, Thorgeirsson SS. 2-Acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: confocal and electron microscopic studies. Hepatology 2004;39:1353–1361CrossRefPubMed

64.

Seki E, Schwabe RF. Hepatic inflammation and fibrosis: Functional links and key pathways. Hepatology 2015;61:1066–1079CrossRefPubMedPubMedCentral

65.

Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 2014;59:2034–2042CrossRefPubMed

66.

Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011;53:2003–2015CrossRefPubMed

67.

Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005;115:56–65CrossRefPubMedPubMedCentral

68.

Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013;58:1461–1473CrossRefPubMed

69.

Xiang S, Dong HH, Liang HF, He SQ, Zhang W, Li CH, et al. Oval cell response is attenuated by depletion of liver resident macrophages in the 2-AAF/partial hepatectomy rat. PLoS ONE 2012;7:e35180CrossRefPubMedPubMedCentral

70.

Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci USA 2013;110:6542–6547CrossRefPubMedPubMedCentral

71.

Van Hul N, Lanthier N, Suner RE, Quinones JA, van Rooijen N, Leclercq I. Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury. Am J Pathol 2011;179:1839–1850CrossRefPubMedPubMedCentral

Title: Liver progenitor cells-mediated liver regeneration in liver cirrhosis
Authors: Haitao Shang
Zhijun Wang
Yuhu Song
Publication date: 01-05-2016
Publisher: Springer India
Published in: Hepatology International / Issue 3/2016
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-015-9693-2

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Liver progenitor cells-mediated liver regeneration in liver cirrhosis

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2016

Genetic and epigenetic mechanisms of NASH

Plasma exchange for acute on chronic liver failure: is there a light at the end of the tunnel?

Hepatitis C virus as a systemic disease: reaching beyond the liver

Association of adiponectin gene polymorphisms and additional gene-gene interaction with nonalcoholic fatty liver disease in the Chinese Han population

Cardiac changes in pediatric liver transplant recipients: are they truly irreversible?

CCL15 overexpression predicts poor prognosis for hepatocellular carcinoma

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page